Modulation of adult hippocampal neurogenesis in laboratory- and wild mice

Secreted Frizzled-Related Protein 3 Regulates Activity-Dependent Adult Hippocampal Neurogenesis

Different regulation of adult hippocampal neurogenesis in Western house mice ( Mus musculus domesticus) and C57BL/6 mice

Objective To investigate the effect of Hes1 upregulation by using an adonoviral vector containing mouse Hes1 gene in adult hippocampal neurogenesis following traumatic brain injury (TBI), a Morris water maze (MWM) test was employed to investigate the spatial learning and memory capacity of adult mice following injury. Methods One hundred and sixty mice were randomly allocated into four groups: sham-PBS group, sham-PBS-TBI group, Ad5-enhanced green fluorescent protein (EGFP)-TBI group, Ad5-Hes1-TBI group. The TBI model mouse was subjected to lateral fluid percussion injury of (202±2) kPa using a pre-calibrated fluid percussion injury device. Then, Ad5-mRNA and PBS were stereotaetic injected into the hippocampus of the adult C57BL/6 mice and their expressions in the hippocampus were detected. Western blotting and real-time fluorescent quantitative polymerase chain reaction (FQ-PCR) methods were employed to detect the expression level of Hes1 on day 3 following TBI. We performed BrdU or DCX immunofluorescence staining on day 3 or 7 post TBI, to investigate the effect of Hes1 upregulation in adult hippocampal neurogenesis following TBI. Results FQ-PCR and Western blotting analysis suggested that Hes1 was up-regulated in overexpression group at mRNA (1.87±0.13 vs. 0.97±0.13, P=0.025) on day 3 post TBI and protein level; Immunofluorescence staining showed that a significant decrease in the total number of BrdU (+ ) and DCX (+ ) cells from the animals with Ad5-mHes1 treated on day 3 or 7 post injury. Morris water maze (MWM) test confirmed that Hes1 overexpression did not lead to a statistically significant change in EL and the target quadrant (P=0.062). Conclusion These results strongly suggested that increased expression of Hes1 may inhibit adult neurogenesis in DG of hippocampus after TBI and did not lead to a statistically significant change in the spatial learning and memory capacity of adult mice following injury. Key words: Hes1; Adult neurogenesis; Traumatic brain injury; Morris water maze

Adult murine hippocampal neurogenesis is inhibited by sustained IL-1β and not rescued by voluntary running

Neurogenesis involves generation of new neurons through finely tuned multistep processes, such as neural stem cell (NSC) proliferation, migration, differentiation, and integration into existing neuronal circuitry in the dentate gyrus of the hippocampus and subventricular zone. Adult hippocampal neurogenesis is involved in cognitive functions and altered in various neurodegenerative disorders, including Alzheimer disease (AD). Ethosuximide (ETH), an anticonvulsant drug is used for the treatment of epileptic seizures. However, the effects of ETH on adult hippocampal neurogenesis and the underlying cellular and molecular mechanism(s) are yet unexplored. Herein, we studied the effects of ETH on rat multipotent NSC proliferation and neuronal differentiation and adult hippocampal neurogenesis in an amyloid β (Aβ) toxin-induced rat model of AD-like phenotypes. ETH potently induced NSC proliferation and neuronal differentiation in the hippocampus-derived NSC in vitro. ETH enhanced NSC proliferation and neuronal differentiation and reduced Aβ toxin-mediated toxicity and neurodegeneration, leading to behavioral recovery in the rat AD model. ETH inhibited Aβ-mediated suppression of neurogenic and Akt/Wnt/β-catenin pathway gene expression in the hippocampus. ETH activated the PI3K·Akt and Wnt·β-catenin transduction pathways that are known to be involved in the regulation of neurogenesis. Inhibition of the PI3K·Akt and Wnt·β-catenin pathways effectively blocked the mitogenic and neurogenic effects of ETH. In silico molecular target prediction docking studies suggest that ETH interacts with Akt, Dkk-1, and GSK-3β. Our findings suggest that ETH stimulates NSC proliferation and differentiation in vitro and adult hippocampal neurogenesis via the PI3K·Akt and Wnt·β-catenin signaling.

Adult hippocampal neurogenesis in Alzheimer's disease: A roadmap to clinical relevance.

Psychiatric and neurologic disorders take an enormous toll on society. Alleviating the devastating symptoms and consequences of neuropsychiatric disorders such as addiction, depression, epilepsy, and schizophrenia is a main force driving clinical and basic researchers alike. By elucidating these disease neuromechanisms, researchers hope to better define treatments and preventive therapies. Research suggests that regulation of adult hippocampal neurogenesis represents a promising approach to treating and perhaps preventing mental illness. Here we appraise the role of adult hippocampal neurogenesis in major psychiatric and neurologic disorders within the essential framework of recent progress made in understanding "normal" adult neurogenesis. Topics addressed include the following: the life cycle of an adult hippocampal stem cell and the implications for aging; links between learning and hippocampal neurogenesis; the reciprocal relationship between cocaine self-administration and adult hippocampal neurogenesis; the role of adult neurogenesis in an animal model of depression and response to antidepressant exposure; the impact of neonatal seizures on dentate gyrus neurogenesis; and the contribution of a schizophrenia-susceptibility gene to adult hippocampal neurogenesis. These topics are discussed in light of the regulation of adult neurogenesis, the relationship to normal neurogenesis in adulthood and aging, and, importantly, the manipulation of neurogenesis to promote mental health and treat mental illness.

Chondroitin sulfate proteoglycan (CSPG) is a candidate regulator of embryonic neurogenesis. The aim of this study was to specify the functional significance of CSPG in adult hippocampal neurogenesis using male mice. Here, we showed that neural stem cells and neuronal progenitors in the dentate gyrus were covered in part by CSPG. Pharmacological depletion of CSPG in the dentate gyrus reduced the densities of neuronal progenitors and newborn granule cells. 3D reconstruction of newborn granule cells showed that their maturation was inhibited by CSPG digestion. The novel object recognition test revealed that CSPG digestion caused cognitive memory impairment. Western blot analysis showed that expression of β-catenin in the dentate gyrus was decreased by CSPG digestion. The amount of CSPG in the dentate gyrus was increased by enriched environment (EE) and was decreased by forced swim stress. In addition, EE accelerated the recovery of CSPG expression in the dentate gyrus from the pharmacological depletion and promoted the restoration of granule cell production. Conversely, the densities of newborn granule cells were also decreased in mice that lacked chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGalNAcT1), a key enzyme for CSPG synthesis (T1KO mice). The capacity of EE to promote granule cell production and improve cognitive memory was impaired in T1KO mice. These findings indicate that CSPG is involved in the regulation of adult hippocampal neurogenesis and suggest that increased synthesis of CSPG by CSGalNacT1 may mediate promotion of granule cell production and improvement of cognitive memory in response to EE.SIGNIFICANCE STATEMENT Chondroitin sulfate proteoglycan (CSPG) is a candidate regulator of embryonic neurogenesis. Here, we specified the role of CSPG in adult neurogenesis in the mouse hippocampus. Digestion of CSPG in the dentate gyrus impaired granule cell production and cognitive memory. Enriched environment (EE) promoted the recovery of CSPG expression and granule cell production from the CSPG digestion. Additionally, adult neurogenesis was impaired in mice that lacked a key enzyme for CSPG synthesis (T1KO mice). The capacity of EE to promote granule cell production and cognitive memory was impaired in T1KO mice. Altogether, these findings indicate that CSPG underlies adult hippocampal neurogenesis and suggest that increased synthesis of CSPG may mediate promotion of granule cell production in response to EE.

Targeting impaired adult hippocampal neurogenesis in ageing by leveraging intrinsic mechanisms regulating Neural Stem Cell activity

Adult hippocampal neurogenesis is a peculiar form of process of neuroplasticity that in recent years has gained great attention for its potential implication in cognition and in emotional behavior in physiological conditions. Moreover, a vast array of experimental studies suggested that adult hippocampal neurogenesis may be altered in various neuropsychiatric disorders, including major depression, where its disregulation may contribute to cognitive impairment and/or emotional aspects associated with those diseases. An intriguing area of interest is the potential influence of drugs on adult neurogenesis. In particular, several psychoactive drugs, including antidepressants, were shown to positively modulate adult hippocampal neurogenesis. Among molecules which could regulate adult hippocampal neurogenesis the NF-κB family of transcription factors has been receiving particular attention from our and other laboratories. Herein we review recent data supporting the involvement of NF-κB signaling pathways in the regulation of adult neurogenesis and in the effects of drugs that are endowed with proneurogenic and antidepressant activity. The potential implications of these findings on our current understanding of the process of adult neurogenesis in physiological and pathological conditions and on the search for novel antidepressants are also discussed.

Adult neurogenesis in hippocampal dentate gyrus (DG) is a complex, but precisely controlled process. Dysregulation of this event contributes to multiple neurological disorders, including major depression. Thus, it is of considerable interest to investigate how adult hippocampal neurogenesis is regulated. Here, we present evidence for neogenin, a multifunctional transmembrane receptor, to regulate adult mouse hippocampal neurogenesis. Loss of neogenin in adult neural stem cells (NSCs) or neural progenitor cells (NPCs) impaired NSCs/NPCs proliferation and neurogenesis, whereas increased their astrocytic differentiation. Mechanistic studies revealed a role for neogenin to positively regulate Gli1, a crucial downstream transcriptional factor of sonic hedgehog, and expression of Gli1 into neogenin depleted NSCs/NPCs restores their proliferation. Further morphological and functional studies showed additional abnormities, including reduced dendritic branches and spines, and impaired glutamatergic neuro-transmission, in neogenin-depleted new-born DG neurons; and mice with depletion of neogenin in NSCs/NPCs exhibited depressive-like behavior. These results thus demonstrate unrecognized functions of neogenin in adult hippocampal NSCs/NPCs-promoting NSCs/NPCs proliferation and neurogenesis and preventing astrogliogenesis and depressive-like behavior, and suggest neogenin regulation of Gli1 signaling as a possible underlying mechanism.

We and others have reported that Notch3 is a regulator of adult hippocampal neurogenesis. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL), the most common genetic form of vascular dementia, is caused by mutations in Notch3. The present study intended to investigate whether there is a correlation between altered adult hippocampal neurogenesis and spatial memory performance in CADASIL transgenic mice. To overcome visual disabilities that hampered behavioral testing of the original mice (on an FVB background) we back-crossed the existing TgN3R169C CADASIL mouse model onto the C57BL/6J background. These animals showed an age-dependent increase in the pathognomonic granular osmiophilic material (GOM) deposition in the hippocampus. Analysis in the Morris water maze task at an age of 6 and 12 months revealed deficits in re-learning and perseverance in the CADASIL transgenic mice. Overexpression of Notch3 alone resulted in deficits in the use of spatial strategies and diminished adult neurogenesis in both age groups. The additional CADASIL mutation compensated the effect on strategy usage but not on adult neurogenesis. In brain bank tissue samples from deceased CADASIL patients we found signs of new neurons, as assessed by calretinin immunohistochemistry, but no conclusive quantification was possible. In summary, while our study confirmed the role of Notch3 in adult neurogenesis, we found a specific effect of the CADASIL mutation only on the reversion of the Notch3 effect on behavior, particularly visible at 6 months of age, consistent with a loss of function. The mutation did not revert the Notch3-dependent changes in adult neurogenesis or otherwise affected adult neurogenesis in this model.

P0113 Maintained microglial homeostasis and adult neurogenesis despite chronic ileocolitis

Adult neurogenesis in the hippocampus subgranular zone is associated with the etiology and treatment efficiency of depression. Factors that affect adult hippocampal neurogenesis have been shown to contribute to the neuropathology of depression. Glutamate, the major excitatory neurotransmitter, plays a critical role in different aspects of neurogenesis. Of the eight metabotropic glutamate receptors (mGluRs), mGluR5 is the most highly expressed in neural stem cells. We previously identified Norbin as a positive regulator of mGluR5 and showed that its expression promotes neurite outgrowth. In this study, we investigated the role of Norbin in adult neurogenesis and depressive-like behaviors using Norbin-deficient mice. We found that Norbin deletion significantly reduced hippocampal neurogenesis; specifically, the loss of Norbin impaired the proliferation and maturation of newborn neurons without affecting cell-fate specification of neural stem cells/neural progenitor cells (NSCs/NPCs). Norbin is highly expressed in the granular neurons in the dentate gyrus of the hippocampus, but it is undetectable in NSCs/NPCs or immature neurons, suggesting that the effect of Norbin on neurogenesis is likely caused by a nonautonomous niche effect. In support of this hypothesis, we found that the expression of a cell-cell contact gene, Desmoplakin, is greatly reduced in Norbin-deletion mice. Moreover, Norbin-KO mice show an increased immobility in the forced-swim test and the tail-suspension test and reduced sucrose preference compared with wild-type controls. Taken together, these results show that Norbin is a regulator of adult hippocampal neurogenesis and that its deletion causes depressive-like behaviors.

Adult neurogenesis is the process by which new neurons are generated in the brains of adults. Since its discovery 50 years ago, adult neurogenesis has been widely studied in the mammalian brain and has provided a new perspective on the pathophysiology of many psychiatric and neurodegenerative disorders, some of which affect memory. In this regard, adult hippocampal neurogenesis (AHN), which occurs in the subgranular zone (SGZ) of the dentate gyrus (DG), has been suggested to play a role in the formation and consolidation of new memories. This process involves many transcription factors, of which cyclic AMP (cAMP)-responsive element-binding protein (CREB) is a well-documented one. In the developing brain, CREB regulates crucial cell stages (e.g., proliferation, differentiation, and survival), and in the adult brain, it participates in neuronal plasticity, learning, and memory. In addition, new evidence supports the hypothesis that CREB may also participate in learning and memory through its involvement in AHN. This review examines the CREB family of transcription factors, including the different members and known signaling pathways. It highlights the role of CREB as a modulator of AHN, which could underlie its function in memory consolidation mechanisms.